Epilepsy is a group of neurological disorders characterized by epileptic seizures. It is a chronic condition of the brain. It is a complex chronic neurological disorder presented in a vast set of diseases that may not have any obvious cause, and is characterized by spontaneous recurrence surges of cortical nerve cell electrical activity in the brain resulting in unprovoked seizures. It is thought the prevalence is about 50 million people worldwide. The Centers for Disease Control and Prevention (CDC) estimate there are around 2.2 million people in the US with epilepsy. The incidence is about 48 of every 100,000 people. Thus, 150,000 people will develop epilepsy in their lifetime. Drug therapy remains ineffective for seizure control in about 30% of patients because either the drugs do not control the seizures or the patients cannot tolerate the side effects.
The seizures episodes can vary from brief and nearly undetectable to long periods of vigorous shaking. In epilepsy, seizures tend to recur and have no immediate underlying cause, while seizures that occur due to a specific cause are not deemed to represent epilepsy. The cause may be a result of brain injury, stroke, brain tumor, drug or alcohol abuse. Genetic mutations are linked to a small proportion of the disease. The diagnosis typically involves ruling out other conditions that might cause similar symptoms such as fainting, and determining if other causes are present such as alcohol withdrawal or electrolyte problems. This may be done by imaging the brain and performing blood tests. Epilepsy can often be confirmed with an electroencephalogram (EEG) but a normal test does not rule out the condition.
Seizures are controllable with medication in about 70% of cases. Some have seizures that do not respond to medication, surgery, neurostimulation or dietary changes, such as the Ketogenic diet. Not all cases are lifelong.
About 60% of seizures are convulsive. Generalized seizures affect both hemispheres of the brain, and account for ⅓ of the cases. Partial seizures (also called focal seizures), affect one hemisphere of the brain in ⅔ of cases, and may then progress to generalized seizures. The other 40% are non-convulsive. For example, there may be an absence seizure (petit mal), a decreased level of consciousness which usually lasts about 10 seconds. About 6% of people have seizures that are triggered by specific stimuli, such as flashing lights and sudden noises. Some seizures occur during sleep. Only about 25% of people with seizures have epilepsy.
Partial seizures are often preceded by an aura. They may include sensory (visual, hearing or small), psychic, autonomic, or motor phenomena. Jerking may start in a specific muscle group and spread to surrounding muscle groups. Non-consciously generated activities and simple repetitive movements like smacking of the lips may occur.
There are six main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, absence, and atonic seizures. Generalized seizures all involve loss of consciousness and typically happen without warning.
Tonic-clonic seizures (grand mal) present with a contraction of the limbs followed by their extension along with arching of the back which lasts 10-30 seconds (the tonic phase). A cry may be heard. Then a shaking of the limbs occurs in unison (clonic phase). Tonic seizures produce constant contractions of the muscles. A person may turn blue from stoppage of breathing. After shaking stops, it may take 10-30 minutes (postictal state) for person to return to normal. There may be loss of bowel or bladder control. The tongue may be bitten.
Myoclonic seizures involve spasms of muscles in either a few areas or all over. Absence seizures can be subtle with only a slight turn of the head or eye blinking. Then the person returns to normal. Atonic seizures involve the loss of muscle activity for more than one second, typically on both sides of the body.
Temporal lobe epilepsy is a chronic neurological condition characterized by recurrent, unprovoked epileptic seizures which originate in the temporal lobe of the brain. They involve sensory changes, such as smelling an unusual odor, or a memory disturbance. The most common cause is mesial temporal sclerosis. Treatment is medication or surgery. Partial seizures account for about 60% of all adult cases. Temporal lobe epilepsy (TLE) is the single most common form of partial seizure.
There is mesial temporal lobe epilepsy (MTLE) arising in the hippocampus, the parahippocampal gyms and the amygdala. The other more rare type, lateral temporal lobe (LTLE), arises in the neocortex at the outer (lateral) surface of the temporal lobe. Autosomal dominant Lateral Temporal Lobe Epilepsy (ADLTLE) is a rare hereditary condition.
Temporal lobe epilepsy and Drug resistant temporal lobe epilepsy is associated with a proinflammatory phenotype in the brain and blood, manifest by activation of the NFκB signaling pathway, and resulting in downstream elevation of proinflammatory cytokines and chemokines such as interleukin-1-beta (IL-1β), interleukin-8 (IL-8) and others (Pollard et al, 2013). Mounting evidence suggests that normal damage control processes in astrocytes and glial cells may contribute to a feed forward loop that promotes epileptic activity (Devinsky et al, 2013; Eisenstein, 2014). Neuronally driven pathological electrical activity may activate the glial cells. Once activated, proinflammatory mediators secreted by the glia may initiate a signaling cascade in neurons that renders them more sensitive to glutamate-induced excitation (During and Spencer, 1993). The inflammatory response may also disrupt the blood-brain-barrier, releasing proinflammatory cytokines and chemokines into the general circulation (Librizzi L, et al. 2012).
The likely involvement of a proinflammatory phenotype for epilepsy has also been implicated in several other recent studies. For example, chronic stimulation of the vagus nerve has been shown to reduce the frequency of adverse events in refractory epilepsy (De Herdt et al, 2009). High levels of various proinflammatory mediators, including IL-8, have been found in surgical excisions of epileptic foci in brains from children with intractable epilepsy (Choi et al. 2009). Injections of kainic acid into the hippocampus to induce seizure activity in rats has resulted in elevated levels of proinflammatory mediators in the rat brain (Lauren et al 2010). In the case of neonatal seizures, elevated levels of proinflammatory mediators have been found in serum (Youn et al, 2012).
Amphiphilic pyridinium compounds have been shown to block TNRα/NFκB signaling and downstream interleukin-8 (IL-8) secretion from cells in vitro (Tchilibon et al. 2005). Optimal inhibitory activities were observed for MRS2481 and its optical isomer MRS2485. These compounds also block the neurotoxic calcium channels formed by amyloid beta peptide (Abeta[1-40]) in neuronal membranes, and protect neurons from Abeta[1-40] dependent cell death (Diaz J C, et al, 2009). Thus these amphiphilic pyridinium compounds have been considered from the vantage point of candidate Alzheimer's Disease drugs. Temporal lobe epilepsy and Drug resistant temporal lobe epilepsy have also been associated with some degree of cognitive impairment, as well as a proinflammatory phenotype.